Hypoxic-ischemic brain damage (HIBD) is one of the major causes of infant death and long-term neurological disturbances, which puts great pressure on families and society. Previous studies have reported that neuroinflammation regulates the pathogenesis of HIBD. MiR-155 has been reported to participate in many brain injuries; however, its direct implication and related mechanisms are not illuminated in HIBD. Herein, we identified that miR-155 plays a vital role in HIBD both in in vitro and in vivo models. We found that miR-155 promoted inflammation and apoptosis via targeting SIRT1 and negatively regulated its expression levels in oxygen-glucose deprivation/reoxygenation (OGD/R) in an in vitro model. Silencing of SIRT1 reversed the effects of miR-155 inhibitor on apoptosis and the NF-κB pathway in OGD/R-treated PC12 cells and microglia (BV2) cells. Moreover, in a neonatal rat HIBD model, miR-155 enhanced apoptosis and inflammation in the brains of rats with HIBD in vivo. Together, our results demonstrated that miR-155 exerted a negative effect in HIBD by targeting SIRT1, which could contribute to the treatment of neonatal patients with hypoxic-ischemic brain damage.